One of the most exciting prospects in modern pharmacology is the potential use of nucleic acids as therapeutic agents. Both gene therapy and pharmacological application of antisense oligonucleotides have evoked interest and excitement in the biomedical research community. However, both nucleic acid based therapeutics can fully achieve its innate potential, several key problems need to be addressed and resolved. Among these key problems are: (1) the need for improved methods to deliver nucleic acids to their sites of actions in cells within tissues: (2) a better understanding of the pharmacodynamics of nucleic acids; that is, understanding the relationship between pharmacological effect and biodistribution for this class of molecules. To address these issues, this Program Project will bring together three investigations from the UNC School of Medicine who are expert in the cellular and molecular pharmacologically of nucleic acids, and three UNC School of Pharmacy investigations expertise in drug transport, delivery, metabolism, and analytical technology. This group of investigators will address fundamental will address fundamental issues affecting the utilization of gene or antisense oligonucleotides as therapeutic agents. The goals of this Program Project will include: (1) development of novel analytical techniques to identify and quantitate genes, oligonucleotides and their fragments in cells and tissues; (2) development of novel and effective strategies for the in vivo delivery of genes and oligonucleotides; (3) development of a standardized methodology to evaluate the effectiveness of gene and of gene and oligonucleotide delivery strategies in the in vivo setting; (4) application of approaches 1-3 to understand the relationship between nucleic acid delivery to target sites and therapeutic outcome in several clinically significant model systems. It is important to realize that there are many common tissues in the therapeutic utilization of genes and of oligonucleotides. Both approaches are best by problems of stability, delivery, effectiveness at the site of action, and of understanding of the relationship between dose and biological effect. Thus, it seems worthwhile to try and develop coherent approach to these tissues that will encompass the therapeutic utilization of both relative low molecular weight nucleic acids (oligonucleotides) and large macromolecules (genes and their associated vectors). In summary, the current Program Project application proposes a pharmacological approach to gene and oligonucleotide therapeutics, one that should lead to a more rational understanding of the field.